Technical Abstract:
Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that circadian clock within the cardiomyocyte plays a role in regulating myocardial metabolism and contractile function. To study the role of circadian clock within the heart, we generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse. Through microarray analysis, we identified 1155 and 362 clock-regulated genes in atria and ventricles, respectively. These genes cluster into 5 major categories: regulation of transcription, transport, signal transduction, protein turnover, and metabolism. In addition, we observed circadian rhythms in cardiac power and efficiency in wild-type hearts ex vivo, which were abolished in CCM hearts. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, and heart rate was reduced in CCM hearts. Furthermore, CCM hearts demonstrated a loss of circadian rhythms in metabolic and functional responses to a workload challenge normally observed in wild-type hearts ex vivo. These studies identify roles for the circadian clock within the cardiomyocyte, exposing direct influences on myocardial gene expression, metabolism, contractile function, and anticipation of workload changes.